Converting from Tetrabenazine to Deutetrabenazine for HD Chorea Appears Safe

Tetrabenazine has been used successfully to treat movement disorders such as Huntington’s disease (HD) chorea and tardive dyskinesia (TD). A recent retrospective observational study of tetrabenazine for various hyperkinetic movement disorders found that all 24 HD chorea patients and 27 of 35 oromandibular TD patients (77%) responded to tetrabenazine. However, the dose that elicited adverse events in this study was considerably lower for TD patients (25 mg) than for HD patients (75 mg).

Deutetrabenazine (Austedo) is a novel molecule that replaces 6 hydrogen atoms in the tetrabenazine molecule with 6 atoms of deuterium, a non-radioactive hydrogen isotope. This replacement gives deutetrabenazine greater stability and a longer half-life than tetrabenazine. It also results in fewer fluctuations in plasma levels than tetrabenazine does and allows the use of lower doses of deutetrabenazine than tetrabenazine. These features may also result in greater patient compliance.

In addition, the US Food and Drug Administration (FDA) approved deutetrabenazine for the treatment of HD-associated chorea in April this year.

To determine the safety and efficacy of switching the treatment of HD patients with chorea from with tetrabenazine to deutetrabenazine, the HD Study Group and the Alternatives for Reducing Chorea in HD Investigators began an ongoing, open-label, single-arm study in 37 HD patients at 13 sites in the US and Australia on December 21, 2013.

Samuel Frank, MD, (pictured) an instructor of neurology at Harvard Medical School, Boston, Massachusetts, is leading the study team. He is also director of the Huntington’s Disease Society of America Center of Excellence at Beth Israel Deaconess Medical Center, Boston, Massachusetts, where he also directs the movement disorders fellowship.

The mean age of the patients in the switching study was 52 years (standard deviation, 12 years). Nearly all (97%) were white, and most (59%) were men.

In the study, the investigators switched patients who had been taking stable doses of tetrabenazine that provided therapeutic benefit to deutetrabenazine treatment. They made the switch overnight and, after the first week, titrated the deutetrabenazine dose once weekly to achieve optimal chorea control. Their aim was to give a dosage of deutetrabenazine that provided comparable systemic exposure to the active metabolites of the previous, stable tetrabenazine dosage.

The study’s main outcome measures for safety included numbers of adverse events, clinical laboratory test results, vital signs, electrocardiogram tracings, and scores on validated safety scales. Its efficacy end points included changes in the Unified HD Rating Scale total maximal chorea score and total motor score.

The investigators found that deutetrabenazine was generally well tolerated and associated with low rates of neuropsychiatric adverse events. They also found that the switch resulted in low rates of dose reduction or suspension attributable to adverse events. In addition, safety scale scores did not indicate that deutetrabenazine therapy resulted in subclinical toxicity.

Regarding deutetrabenazine efficacy, chorea control indicated by total maximal chorea score remained stable at week 1 and improved from baseline by 2 points at week 8 (P < 0.001).

These findings led the investigators to conclude that in patients with HD chorea, overnight conversion to deutetrabenazine resulted in a favorable safety profile and effectively maintained chorea control.

The study, “Safety of converting from tetrabenazine to deutetrabenazine for the treatment of chorea,” was published online in July in JAMA Neurology.

A report on the study of tetrabenazine for TD and HD chorea, “Tetrabenazine in treatment of hyperkinetic movement disorders: an observational study,” appeared early this year in Therapeutic Advances in Neurological Disorders.

Related Coverage:

KINECT Analysis Finds Differently Diagnosed TD Affects Patients Differently

AIM-TD Study: Deutetrabenazine Fixed Doses Reduced Tardive Dyskinesia

Deutetrabenazine Able To Limit Tardive Dyskinesia Effects